Structure Report for: 4AZ0

Ruf, S., Buning, C., Schreuder, H., Horstick, G., Linz, W., Olpp, T., Pernerstorfer, J., Hiss, K., Kroll, K., Kannt, A., Kohlmann, M., Linz, D., Hubschle, T., Rutten, H., Wirth, K., Schmidt, T., Sadowski, T

Title: Novel beta-amino acid derivatives as inhibitors of cathepsin A.
Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K and Sadowski T <7 more author(s)> Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K, Kannt A, Kohlmann M, Linz D, Hubschle T, Rutten H, Wirth K, Schmidt T, Sadowski T (- 7)
Ref: Journal of Medicinal Chemistry, 55:7636, 2012 : PubMed
Abstract


ESTHER: Ruf_2012_J.Med.Chem_55_7636
PubMedSearch: Ruf 2012 J.Med.Chem 55 7636
PubMedID: 22861813
Gene_locus related to this paper: human-CTSA
Inhibitor(s) related to this paper: Ebelactone-B, CHEMBL3145341, CHEMBL2171392

Abstract

Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel beta-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials.